Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor

XANTHIPPE: Examining the Effect of Ticagrelor on Platelet Activation, Platelet-Leukocyte Aggregates, and Acute Lung Injury in Pneumonia

The hypothesis to be tested is that ticagrelor (Brilinta™) will reduce platelet activation and markers of inflammation in patients with pneumonia.

While it is well established that platelets are integral to hemostasis, more recent evidence points to an important role for platelets in inflammation and immunity. Platelet activation and sequestration in pulmonary tissue is a key feature in inflammatory or infectious states such as sepsis and acute respiratory distress syndrome (ARDS). Platelets may mediate acute lung injury (ALI) by recruiting neutrophils, triggering neutrophil extracellular DNA nets, and releasing granule contents and microparticles. Anti-platelet therapy in this setting may prevent platelet activation, platelet - leukocyte aggregate formation, and inflammation.

The objective of this pilot study is to determine if ticagrelor therapy in individuals with pneumonia reduces markers of platelet activation, platelet-leukocyte aggregates, inflammation, acute lung injury, and lung mechanics. Because the benefit of anti-platelet therapy may the greatest in patients with more significant lung injury, the investigators will enroll patients with community-acquired pneumonia (CAP) requiring hospitalization or patients with hospital acquired pneumonia (HAP) within 48 hours of diagnosis. On study day 1, subjects will be randomized to receive ticagrelor (180 mg load and 90 mg BID) or placebo. Study medication (ticagrelor or placebo) will be administered twice daily on days 2 - 7 or until hospital discharge, if sooner than 7 days. Blood will be collected and assays performed on day 1 prior to study medication administration (baseline), day 2, 3, 7, day of discharge (if before 7 days), and 30 days for analysis of platelet count, markers of platelet activation, platelet - leukocyte interactions, biomarkers of inflammation, and measurements of lung mechanics.

Inclusion Criteria:

• Subjects must be 18 years of age or older

• Subjects must diagnosed with Community acquired pneumonia (CAP) or hospital acquired pneumonia (HAP) within 48 hours of diagnosis or presentation to hospital.

• Pneumonia will be defined as patients with a new radiographic finding(s) consistent with pneumonia and at least two of the following signs.

  1. Cough
  2. Fever: axillary temperature >37.5ºC or tympanic temperature >38.5ºC
  3. Hypothermia: axillary temperature <34ºC or tympanic temperature <35ºC.
  4. Purulent sputum production or respiratory secretion.
  5. Total peripheral white blood cell (WBC) count >10,000/mm3; or >15% band forms, regardless of total peripheral white count; or leucopenia with total WBC < 4500/mm
  6. Auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony)
  7. Hypoxemia - defined as partial O2 pressure <60mmHg while the patient was breathing normal air or a decrease in the partial O2 pressure of >= 25% from an initial range.

Exclusion Criteria:

1. Contraindication to ticagrelor (hypersensitivity or reaction to ticagrelor or another P2Y12 antagonist)
2. Active bleeding or major bleeding history (e.g. intracranial bleeding)
3. Clinically important anemia or thrombocytopenia (platelet count <30)
4. Surgery within 30 days or anticipated major surgery (Thoracic, Abdominal, Brain; placement of lines, tracheostomy, and chest tubes are not considered major).
5. Oral anticoagulant therapy that cannot be stopped.
6. Inability or unwillingness of treating physician to reduce dose of aspirin to 81mg.
7. Fibrinolytic therapy in the last 24 hours.
8. Increased risk of bradycardic events - 2nd or 3rd degree heart block, bradycardia induced syncope - unless pacemaker in place.
9. Underlying immunodeficiency (HIV, neutropenia, receiving immunomodulating agents, active hematologic malignancy, functional or anatomical asplenia and hypogammaglobulinemia).
10. Moderate or severe liver disease defined by Child Pugh score >7 using data from outpatient setting or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 fold upper limits of normal.
11. Renal dialysis
12. Concomitant therapy with strong CYP3A inhibitors; ketoconazole, itraconazole, voriconazole, saquinavir, nelfinavir, indinavir, or atazanavir.
13. Concomitant therapy with CYP3A substate with narrow therapeutic window: cyclosporin, quinidine.
14. Concomitant therapy with CYP3A inducer; rifampin/rifampicin, phenytoin, carbamazepine.
15. Pregnancy or lactation
16. Active treatment for cancer.